In general, retroviruses have the proteins Gag, Pol, and Env in common. In addition to these proteins, human immunodeficiency virus (HIV) has viral-specific regulatory proteins and accessory proteins. Nef is one of the accessory proteins which is specific to HIV-1, HIV-2 and SIV (simian immunodeficiency virus) and is synthesized in the early stage of the virus replication. The protein was designated Nef at the beginning since it is deemed that Nef is a negative factor which decreases the replication of the virus. However, afterward, it has been suggested that Nef works as a positive regulator for HIV replication by experiments testing the pathogenesis of Nef-deleted SIV mutant in the rhesus monkey. Nef is recognized anew as an important factor for holding a key to developing the pathogenesis of AIDS. See, Fujii et al, Saibo Kogaku, vol. 16, No. 1, 94-99 (1997)].
As mentioned in detail in the above article by Fujii, et al., the important functions of Nef in vivo are thought to be: (1) promotion of virus replication, (2) down regulation of CD4 molecularly, and (3) cytotoxicity to T cells. With regard to the virus infection, it has been known that Nef has an affinity to cell membranes, is necessary for virus adsorption and the invasion of the virus into cells, and participates in viral DNA synthesis. Concerning the cytotoxicity to T cells, apoptosis of the cells is induced when Nef is bound to the surface of CD4.sup.+ T cells of intestinal lymph node and peripheral blood and the cross-linking of the Nef molecule is caused by an anti-Nef antibody. Therefore, it is strongly suggested that binding of Nef to a Nef receptor on the CD4.sup.+ T cells greatly participates in depletion of CD4.sup.+ T cells in patients with HIV. Namely, pathogenesis of AIDS relates to the binding of Nef and its receptor. In addition, there is a report which suggests that Nef inhibits the production of cytokine resulting in the suppression of the immune system.
Most of the therapeutic agents for AIDS which have been used and developed so far are reverse transcriptase inhibitors such as azidothymidine, ddI, etc. and protease inhibitors, which are drugs which inhibit the growth of virus directly. In addition to these drugs, there are immunopotentiators which activate the function of the immune system depraved by AIDS and chemotherapeutic agents aimed at the treatment of symptoms such as malignant tumors and opportunistic infections caused by AIDS. Based on the above-mentioned findings on Nef, a drug which inhibits T cell apotosis caused by Nef and thereby suppresses the onset of AIDS has aroused public attention as a novel inhibitor for AIDS with a different action mechanism from those of the above-mentioned reverse transcriptase inhibitors and protease inhibitors.
Various kinds of reverse transcriptase inhibitors and protease inhibitors have been developed as a strategy to suppress AIDS. A cocktail therapy where two or more of such inhibitors are combined has been promoted in order to avoid the problems caused by the development of HIV mutation. However, there is still a strong demand for pharmaceutical agents which have a mechanism of action to suppress AIDS in addition to the direct inhibitors of viral growth. It has been recently clarified that Nef participates in invasion of the virus into cells and induces apoptosis of CD4.sup.+ T cells which play an important role in the disappearance of CD4.sup.+ cells in patients with HIV. The action is triggered by the binding of Nef to Nef-attachable protein (hereinafter, referred to as Nap) on cell walls. The actual existence of Nap has been anticipated by experiments showing the binding of Nef to CD4.sup.+ T cells or the like, however, Nap has not been specified yet.
The present invention provides a Nef-attachable protein (Nap) on the CD4.sup.+ T cell membrane which can recognize and be bound to Nef to play an important role in the onset of AIDS, a gene encoding Nap, and a monoclonal antibody against said protein.